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Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication

Annelies Paridaens (UGent) , Sarah Raevens (UGent) , Isabelle Colle (UGent) , Eliene Bogaerts (UGent) , Yves-Paul Vandewynckel (UGent) , Xavier Verhelst (UGent) , Anne Hoorens (UGent) , Leo A van Grunsven, Hans Van Vlierberghe (UGent) , Anja Geerts (UGent) , et al.
(2017) LIVER INTERNATIONAL. 37(5). p.748-756
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Abstract
BACKGROUND & AIMS: Acetaminophen overdose in mice is characterized by hepatocyte endoplasmic reticulum stress, which activates the unfolded protein response, and centrilobular hepatocyte death. We aimed at investigating the therapeutic potential of tauroursodeoxycholic acid, a hydrophilic bile acid known to have anti-apoptotic and endoplasmic reticulum stress-reducing capacities, in experimental acute liver injury induced by acetaminophen overdose. METHODS: Mice were injected with 300 mg/kg acetaminophen, 2 hours prior to receiving tauroursodeoxycholic acid, N-acetylcysteine or a combination therapy, and were euthanized 24 hours later. Liver damage was assessed by serum transaminases, liver histology, terminal deoxynucleotidyl transferase dUTP nick end labelling staining, expression profiling of inflammatory, oxidative stress, unfolded protein response, apoptotic and pyroptotic markers. RESULTS: Acetaminophen overdose resulted in a significant increase in serum transaminases, hepatocyte cell death, unfolded protein response activation, oxidative stress, NLRP3 inflammasome activation, caspase 1 and pro-inflammatory cytokine expressions. Standard of care, N-acetylcysteine and, to a lesser extent, tauroursodeoxycholic treatment were associated with significantly lower transaminase levels, hepatocyte death, unfolded protein response activation, oxidative stress markers, caspase 1 expression and NLRP3 levels. Importantly, the combination of N-acetylcysteine and tauroursodeoxycholic acid improved serum transaminase levels, reduced histopathological liver damage, UPR-activated CHOP, oxidative stress, caspase 1 expression, NLRP3 levels, IL-1β levels and the expression of pro-inflammatory cytokines and this to a greater extend than N-acetylcysteine alone. CONCLUSIONS: These findings indicate that a combination strategy of N-acetylcysteine and tauroursodeoxycholic acid surpasses the standard of care in acetaminophen-induced liver injury in mice and might represent an attractive therapeutic opportunity for acetaminophen-intoxicated patients.
Keywords
endoplasmic reticulum stress, hepatotoxicity, paracetamol, tauroursodeoxycholic acid, ENDOPLASMIC-RETICULUM STRESS, INDUCED LIVER-INJURY, UNFOLDED PROTEIN RESPONSE, ER STRESS, INDUCED APOPTOSIS, CELL-DEATH, INDUCED HEPATOTOXICITY, HEPATOCYTE DEATH, MICE, GLUTATHIONE

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Citation

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Chicago
Paridaens, Annelies, Sarah Raevens, Isabelle Colle, Eliene Bogaerts, Yves-Paul Vandewynckel, Xavier Verhelst, Anne Hoorens, et al. 2017. “Combination of Tauroursodeoxycholic Acid and N-acetylcysteine Exceeds Standard Treatment for Acetaminophen Intoxication.” Liver International 37 (5): 748–756.
APA
Paridaens, Annelies, Raevens, S., Colle, I., Bogaerts, E., Vandewynckel, Y.-P., Verhelst, X., Hoorens, A., et al. (2017). Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication. LIVER INTERNATIONAL, 37(5), 748–756.
Vancouver
1.
Paridaens A, Raevens S, Colle I, Bogaerts E, Vandewynckel Y-P, Verhelst X, et al. Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication. LIVER INTERNATIONAL. 2017;37(5):748–56.
MLA
Paridaens, Annelies, Sarah Raevens, Isabelle Colle, et al. “Combination of Tauroursodeoxycholic Acid and N-acetylcysteine Exceeds Standard Treatment for Acetaminophen Intoxication.” LIVER INTERNATIONAL 37.5 (2017): 748–756. Print.
@article{8174562,
  abstract     = {BACKGROUND \& AIMS: Acetaminophen overdose in mice is characterized by hepatocyte endoplasmic reticulum stress, which activates the unfolded protein response, and centrilobular hepatocyte death. We aimed at investigating the therapeutic potential of tauroursodeoxycholic acid, a hydrophilic bile acid known to have anti-apoptotic and endoplasmic reticulum stress-reducing capacities, in experimental acute liver injury induced by acetaminophen overdose.
METHODS: Mice were injected with 300 mg/kg acetaminophen, 2 hours prior to receiving tauroursodeoxycholic acid, N-acetylcysteine or a combination therapy, and were euthanized 24 hours later. Liver damage was assessed by serum transaminases, liver histology, terminal deoxynucleotidyl transferase dUTP nick end labelling staining, expression profiling of inflammatory, oxidative stress, unfolded protein response, apoptotic and pyroptotic markers.
RESULTS: Acetaminophen overdose resulted in a significant increase in serum transaminases, hepatocyte cell death, unfolded protein response activation, oxidative stress, NLRP3 inflammasome activation, caspase 1 and pro-inflammatory cytokine expressions. Standard of care, N-acetylcysteine and, to a lesser extent, tauroursodeoxycholic treatment were associated with significantly lower transaminase levels, hepatocyte death, unfolded protein response activation, oxidative stress markers, caspase 1 expression and NLRP3 levels. Importantly, the combination of N-acetylcysteine and tauroursodeoxycholic acid improved serum transaminase levels, reduced histopathological liver damage, UPR-activated CHOP, oxidative stress, caspase 1 expression, NLRP3 levels, IL-1\ensuremath{\beta} levels and the expression of pro-inflammatory cytokines and this to a greater extend than N-acetylcysteine alone.
CONCLUSIONS: These findings indicate that a combination strategy of N-acetylcysteine and tauroursodeoxycholic acid surpasses the standard of care in acetaminophen-induced liver injury in mice and might represent an attractive therapeutic opportunity for acetaminophen-intoxicated patients.},
  author       = {Paridaens, Annelies and Raevens, Sarah and Colle, Isabelle and Bogaerts, Eliene and Vandewynckel, Yves-Paul and Verhelst, Xavier and Hoorens, Anne and van Grunsven, Leo A and Van Vlierberghe, Hans and Geerts, Anja and Devisscher, Lindsey},
  issn         = {1478-3223},
  journal      = {LIVER INTERNATIONAL},
  keyword      = {endoplasmic reticulum stress,hepatotoxicity,paracetamol,tauroursodeoxycholic acid,ENDOPLASMIC-RETICULUM STRESS,INDUCED LIVER-INJURY,UNFOLDED PROTEIN RESPONSE,ER STRESS,INDUCED APOPTOSIS,CELL-DEATH,INDUCED HEPATOTOXICITY,HEPATOCYTE DEATH,MICE,GLUTATHIONE},
  language     = {eng},
  number       = {5},
  pages        = {748--756},
  title        = {Combination of tauroursodeoxycholic acid and N-acetylcysteine exceeds standard treatment for acetaminophen intoxication},
  url          = {http://dx.doi.org/10.1111/liv.13261},
  volume       = {37},
  year         = {2017},
}

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